Inflammation is often induced by proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1α, IL-1β, IL-6, platelet-activating factor (PAF), macrophage migration inhibitory factor (MIF), HMGB1 and other compounds. These proinflammatory cytokines are produced by several different cell types, most importantly immune cells (for example, monocytes, macrophages and neutrophils), contributing to various disorders during the early stages of an inflammatory cytokine cascade.
The early pro-inflammatory cytokines (e.g., TNF, IL-1, etc.) mediate inflammation, and induce the late release of high mobility group-1 (HMG1) (also known as HMG-1 and HMGB1), a protein that accumulates in serum and mediates delayed lethality and further induction of early pro-inflammatory cytokines.
Tumor Necrosis Factor (TNF) isoforms α and β are soluble proteins produced by monocytes and macrophages in response to endotoxin or other stimuli. Cells other than monocytes or macrophages also make TNFα. For example, human non-monocytic tumor cell lines produce TNFα. (For recent reviews on TNF family, see Lin A, et al., Aging Cell. 2002 December; 1(2):112-6 and Baugh J. et al., Curr Opin Drug Discov Devel. 2001 September; 4(5):635-50.)
Upon binding to its cognate receptor, TNFα activates both apoptosis and NF-kB-dependent survival pathways. TNF causes pro-inflammatory actions which result in tissue injury, such as inducing pro-coagulant activity on vascular endothelial cells, increasing the adherence of neutrophils and lymphocytes, and stimulating the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells. (Pober, et al., J. Immunol. 136:1680 (1986); Pober, et al., J. Immunol. 138:3319 (1987); Camussi, et al., J. Exp. Med. 166:1390 (1987)).
TNF is also associated with infections, immune disorders, neoplastic, autoimmune and graft-versus host pathologies. TNF can mediate cachexia in cancer, infectious pathology, and other catabolic states. (Kern, et al., (J. Parent. Enter. Nutr, 12:286-298 (1988)). TNF also plays a central role in gram-negative sepsis and endotoxic shock. Endotoxin strongly activates monocyte/macrophage production and secretion of TNF and other cytokines. (Michie, et al., Br. J. Surg. 76:670-671 (1989); Debets, et al., Second Vienna Shock Forum, p. 463-466 (1989); Simpson, et al., Crit. Care Clin. 5:27-47 (1989); Kombluth, et al., J. Immunol. 137:2585-2591 (1986)).
HMGB1 is a member of a family of DNA-binding proteins termed high mobility group (HMG) and has been implicated as a cytokine mediator of delayed lethality in endotoxemia (Wang et al., Science 285: 248-251, 1999; WO 00/47104). That work demonstrated that bacterial endotoxin (lipopolysaccharide (LPS)) activates monocytes/macrophages to release HMGB1 as a late response to activation, resulting in elevated serum HMGB1 levels that are toxic. Antibodies against HMGB1 prevent lethality of endotoxin even when antibody administration is delayed until after the early cytokine response. (ibid.) HMGB1 has also been implicated in mediating other inflammatory disorders such as endotoxin-induced lung edema, sepsis and hemorrhagic shock. (See, e.g., U.S. Pat. Nos. 6,448,223 and 6,468,533.)
There is a need for new therapeutic agents which suppress the production, release and/or activity of inflammatory cytokines such as TNF and HMGB1 and which therefore can be used in treatment of inflammatory disorders.